Integrated in Silico Models for the Prediction of Human Repeated Dose Toxicity of Cosmetics to Optimise Safety – COSMOS

Background

The use of animals (in vivo experiments) to test chemicals for use as cosmetic ingredients has been forbidden in the EU since the 11th of March 2013. Therefore, there is a need for alternative risk assessment methods and the ‘Threshold of Toxicological Concerns’ (TTC) approach is one of them. This threshold was explored as part of COSMOS. Though COSMOS has come to an end, ILSI Europe is still tackling the question of alternatives to animal testing via our new activity – see page 84 for more information.
TTC is a widely applied risk assessment approach that establishes a human exposure threshold value for chemicals below which there is a low probability of an appreciable risk to human health. The current TTC approach was developed from an oral toxicity database and its applicability to dermal exposure is under consideration. The TTC concept is a potential alternative to the use ofin vivo studies.

Objectives

COSMOS assessed how the current TTC approach could be applied to cosmetic ingredients, and how to extrapolate from oral to dermal route exposure, which is particularly relevant for cosmetics. The COSMOS project was a unique collaboration, addressing the safety assessment needs of the cosmetics industry, without the use of animals.

Role of ILSI Europe

ILSI Europe was a partner in the COSMOS project contributing via 2 expert groups of the Threshold of Toxicological Concern Task Force:

Criteria to apply the TTC approach to cosmetic ingredients;

Evaluation of oral-to-dermal extrapolation.

Detailed information about the expert groups is provided and illustrated overleaf.

Expert Group 1

Development of Criteria to be Applied in the Extension of the Current TTC Approach to Cosmetics Ingredients

Objectives

An oral toxicity database of cosmetics ingredients was developed. The database could ultimately be used to confirm that the current TTC tiers are applicable to cosmetic ingredients. The database is a combination of existing public data plus new data harvested for cosmetic ingredients by COSMOS.

Activity

The expert group determined the No Observed Adverse Effect Level (NOAEL) / Lowest Observed Adverse Effect Level (LOAEL) for the chemicals included in the database. The criteria to be used have been clearly identified and are documented in an internal COSMOS report.

The purpose was to:

Evaluate the new structural categories applicable for cosmetics ingredients;

Recommend and compare new thresholds with the current levels.

Output

This expert group advised on inclusion criteria for chemicals and toxicological studies. These criteria will help in creating a toxicity database for cosmetics and will support the evaluation of the data collection. All this information is now available on the COSMOS website.

Expert Group 2

Evaluation of Oral-to-Dermal Extrapolation

Objectives

The aim of the activity is to adapt the oral TTC approach and extend its applicability to cosmetics that are applied to the skin, in cases where there are no toxicity data and no or limited dermal absorption data. Also the importance of differences in bioavailability between oral and dermal exposures is addressed.

Activity

The group developed a dermal absorption database containing data of recent in vitro and in vivo dermal absorption studies from peer-reviewed literature and from COSMOS collaborators. Cosmetic chemicals of interest were grouped hierarchically according to their metabolism in skin with the information required for each chemical. Several scenarios of bioavailability of those chemicals were proposed.

Output

A decision-tree approach was developed to assess systemic availability, based on estimated usage/skin exposure for a cosmetic scenario. The maximum possible dermal absorption is derived from the maximal flux prediction to estimate the systemic dose ranking against oral TTC, incorporating structural categories and Cramer classification (R. Kroes, et al. 2007). The manuscript‘Assessing the safety of cosmetic chemicals: consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern)’ has been submitted to Regulatory Toxicology and Pharmacology.

Contribution of ILSI Europe – COSMOS Experts Groups

Both expert groups have jointly contributed to the following 4 deliverables:

A first publication entitled ‘Assessing the Safety of Cosmetic Chemicals: Consideration of a Flux Decision Tree to Predict Dermally Delivered Systemic Dose for Comparison with Oral TTC’, based on the findings of the expert groups, was accepted for publication in the journal Regulatory Toxicology and Pharmacology, recently. In addition, a second peer-reviewed manuscript‘Thresholds of Toxicological Concern for Substances Used in Cosmetics’ will be submitted for publication soon.

Impact

COSMOS was one of six projects forming the SEURAT-1 cluster. The Research Initiative is a first step to addressing the long term strategic target of Safety Evaluation Ultimately Replacing Animal Testing (SEURAT). It is called SEURAT-1, indicating that more steps have to be taken before the final goal will be reached. SEURAT-1 is developing knowledge and technology building blocks required for the development of solutions for the replacement of current repeated dose systemic toxicity testing in vivoused for the assessment of human safety. SEURAT-1 is the largest EU initiative ever undertaken on alternative methods. The cluster comprises 70 European research partners that are co-financed (equally) through a unique public-private partnership between the European Commission (Framework Programme 7 administered by DG Research & Innovation) and Cosmetics Europe.

The main aim of COSMOS was to develop freely available (open access) tools and workflows to predict the harmful long-term effects of cosmetic ingredients on humans. The project delivered guidelines and recommendations to expand the current TTC approach in order to broaden its applicability and regulatory acceptance for cosmetic ingredients. The COSMOS Symposium on Computational Tools for Safety Assessment was held on 9 September 2015 in Liverpool, UK. The one-day workshop event presented an overview of the outcome and legacy of the EU COSMOS Project.

The presentations were broadcast live via webcast to an international audience as well as being recorded. The recorded presentations are available here.